Books
in black and white
Main menu
Home About us Share a book
Books
Biology Business Chemistry Computers Culture Economics Fiction Games Guide History Management Mathematical Medicine Mental Fitnes Physics Psychology Scince Sport Technics
Ads

Solid-phase organik syntheses - Burdges K.

Burdges K. Solid-phase organik syntheses - John Wiley & Sons, 2000. - 283 p.
ISBN 0-471-22824-9
Download (direct link): phaseorganicsynthesis2000.pdf
Previous << 1 .. 24 25 26 27 28 29 < 30 > 31 32 33 34 35 36 .. 82 >> Next

Experience has shown that the most time-consuming steps in library synthesis typically involve demonstrating the feasibility of generating a particular central core structure on solid support as well as rehearsing the compatibility of variously functionalized monomers with the synthetic scheme. The assembly of a highly diverse library portfolio based on different central scaffolds is, therefore, bound to involve a significant investment in terms of time and manpower. With this in mind, it is attractive to consider synthetic strategies that provide access to multiple, structurally diverse core structures starting from common, fundamental intermediates and to use similar sequences of synthetic transformations in conjunction with the appropriate monomer inputs. One such intermediate is the imine, and we have previously described its exploitation in a variety of solid-phase cycloaddition and condensation reactions.3 Another example of a versatile synthon is 4-fluoro-3-nitrobenzoic acid 1. We and other groups have now shown that a variety of benzofused heterocycles can be derived from resin-bound 4-fluoro-3-nitrobenzoic acids la,b via solid-phase nucleo-philic aromatic substitution (viz. S^Ar) reactions with either sulfur or nitrogen nucleophiles (Scheme 1).
3.1. INTRODUCTION
2b (R=Me)
Scheme 1.
84 BENZOFUSED HETEROCYCLES VIA SOLID-PHASE SAR REACTIONS
This chapter will give an account of work performed to date in this area, covering solid-phase syntheses of l,5-benzothiazepin-4-ones 2a,b,4 1,6-benzothiazocin-5-ones ,5 1,5-benzodiazepin-2-ones 4,67 4-alkoxy-1,4-thiazin-3-ones 5,5 quinoxalin-2-ones 6,5A9 benzimidazolones 7,10 2-alkylthiobenzimidazoles 8," and 2-alkylaminomethylbenzimidazoles 9.12
3.2. FORMATION OF [6,7]- AND [6,8]-FUSED SYSTEMS
3.2.1. 1,5-Benzothiazepin-4-ones (2) and 1,6-Benzothiazocin-5-ones (3)
Along with the dihydropyridines (e.g., nifedipine) and phenylalkylamines (e.g., verapamil), 1,5-benzothiazepin-4-ones (e.g., diltiazem) are among the most widely used drugs in the treatment of cardiovascular disorders. They are calcium antagonists interacting with the L-type voltage-gated Ca2+ channel.13'14 Many solution-phase protocols for synthesis of 1,5-benzo-thiazepin-4-ones can be found in the literature,15 but no solid-phase synthesis has been reported to date. We envisaged a synthetic approach to
1,5-benzothiazepinones 2a that involved nucleophilic aromatic substitution reactions on solid support, in which the basic benzothiazepine skeleton was to be assembled from a resin-bound 4-fluoro-3-nitrobenzoic acid 1 and a suitably protected form of cysteine (Scheme 2).4
Exposure of la to a solution containing 1.5 equivalents of Fmoc-L-cysteine 10 and DIEA in DMF16 resulted in smooth conversion to the 2-nitro-thioether 11, which was subsequently reduced to the corresponding primary aniline 12 using SnCl2-2H20 in DMF.17 In accordance with literature data,18 the subsequent reductive alkylation of 12 proved to be problematic due to the poor nucleophilicity of the aniline nitrogen as compared with that of aliphatic amino groups. Particularly low yields were obtained for aromatic aldehydes bearing electron-donating and/or ortho substituents, as well as for aliphatic aldehydes. After extensive optimization, conditions were identified where resin 12 was reacted with a large molar excess of aldehyde in a mixture of trimethylorthoformate,19'20 DMF, MeOH, and acetic acid at 50C. Using this protocol, a variety of aromatic aldehydes cleanly afforded the corresponding secondary anilines 14 (Figure 3.1). The only significant side product occasionally present in minor amounts (510%) was the jV-methyl-aniline 13, arising from incorporation of the
3.2. FORMATION OF [6,7]- AND [6,8]-FUSED SYSTEMS
(Resin is ArgoGel/Rink)
(i) L-FMOC-Cys (L-10) DIEA, DMF
(ii) SnCI2*2H20, DMF
(i) R1CHO CH(OMe)3, DMF HOAc, MeOH
(ii) NaCNBH3, THF
(iii) 2% H0Ac/H20
11 (R,R' = 0)
12 (R,R = H)
13 (R = H, R' = Me)
COR
NHFMOC
14 (R = OH)
15 (R = N(/-Pr)-CO-NH(/-Pr))
(i) DIC, Benzene, CH2CI2
(ii) Piperidine, DMF
16 (R = FMOC)
17 (R = H)
(i) R2-CHO, HOAc, CH(OMe)3
(ii) NaCNBH3, THF
(iii) TFA, CH2CI2
and/or
(i) R3-COOH, DIC, DMAP, DMF
(ii) TFA, CH2CI2
and/or
(i) r4-so2ci, nmm, ch2ci2
(ii) TFA, CH2CI2
and/or
(i) R5-NCO, NMM, CH2CI2
(ii) TFA, CH2CI2
HpN
NHR
,2
2A (R = CH2R'
2B (R = COR3)
2C (R = S02R4) 2D (R = CONHR5)
Scheme 2.
86 BENZOFUSED HETEROCYCLES VIA SOLID-PHASE SWAR REACTIONS
CHO NO/^/CHO
CHO

,
CHO
CHO
KCH/=\ CrCH0
O'* Cr" jy
CHO
hL.CHO
CHO
A
CHO
A


CHO
CHO
"CHO
CHO
CHO
Figure 3.1. Selection of aldehydes R CHO successfully used in the reductive alkylation of primary aniline 12.
methine-carbon of the orthoformate.21,22 Electron-rich aldehydes, such as N-alkylamino-benzaldehydes and TV-methylated indole- and pyrrole-car-boxaldehydes, however, failed to afford any of the desired secondary anilines.
Previous << 1 .. 24 25 26 27 28 29 < 30 > 31 32 33 34 35 36 .. 82 >> Next